Summary of Work: The glucocorticoid hormone action group studies how environmental stress activates signal transduction pathways. Our primary interest is in the glucorticoid receptor, the only steroid receptor necessary for human life. Recent studies have shown that a mutual antagonism exists between pro-inflammatory cytokine and glucocorticoid signaling. Specifically, signal transduction by the glucocorticoid receptor is impaired in cells with active nuclear NFkB, and signal transduction by NFkB is impaired in cells when the glucocorticoid receptor is active. We are studying the mechanism of this antagonism at the level of protein/protein interactions. A second effort is aimed at understanding what role phosphorylation has in glucocorticoid receptor signal transduction. Interestingly, glucocorticoid receptor phosphorylation modulates receptor transcriptional activation but not repression. Recent work links phosphorylation to ubiquitin mediated proteosomal degradation. Another focus of our work is on glucocorticoid receptor down regulation which leads to resistance to steroids. We have shown that the glucocorticoid receptor represses the expression of its own gene. This repression occurs via a consequence of the direct interaction of the glucocorticoid receptor with two novel intragenic binding sites within the gene and to destabilization of the glucocorticoid receptor mRNA. Mutational analyses of these sites are being performed. Finally, we have recently described the widespread expression of a second form of human glucocorticoid receptor. This receptor, termed hGRBeta, is an alternatively spliced product from the same gene and functions as a strong dominant negative inhibitor of glucocorticoid receptor signaling. This receptor shows strong expression in epithelia cells and has been shown to be overexpressed in several human diseases including steroid resistant asthma.